Nitroalkanes reaction with aldehydes

Matsumoto et al. have reported the first example of a diastereoselective nitro-aldol reaction of optically active A,(V-dibenzyl a-amino aldehydes 150 with nitroalkanes 151 under high pressure without a catalyst (Scheme 7.38). The reactions occurred at 0.8 GPa (room temperature, 12h) and gave mixtures of diastereomers 152 and 153 in good yields and with high optical purity under atmospheric pressure 150 did not react with 151. Very high diastereoselectivity (152/153 = 99) was observed in the reaction of 150a with 2-nitropropane (151c). 

The above are examples of the Claisen - Schmidt reaction. The formation of p-nitrostyrenes by reaction of nitroalkanes with aromatic aldehydes in the presence of aqueous alkali may be included under the Claisen- hmidt condensation ... 

The 3-nitro alcohols are generally obtained in good yield by the reaction of aldehydes with nitroalkanes in the presence of a catalytic amount of base. When aryl aldehydes are used, the (3-nitro alcohols formed may undergo elimination of water to give aryl nitroalkenes. Such side reactions are not always disadvantageous, for nitroalkenes are sometimes the ultimate target for the Henry reaction. The choice of reaction conditions is important to stop the reaction at the stage of 3-nitro alcohols in aromatic cases. 

In general, base-catalyzed reactions of aromatic aldehydes with nitroalkanes give nitroalkenes directly (Knoevenagel reaction).54 The reaction is very simple heating a mixture of aromatic aldehydes, nitroalkanes, and amines in benzene or toluene for several hours using a Dean-Stark water separator gives the desired nitroalkenes in good yield, as shown in Eqs. 3.31-3.34.54-58... 

The addition of alkoxides to 2-nitro-l-phenylthio-l-alkenes affords P-nitro-aldehyde acetals.276 The reaction of the same nitroalkenes with amines gives nitroenamines.270 They are important intermediates for organic synthesis and are generally prepared by the reaction of nitroalkanes with triethylorthoformate in the presence of alcohols or secondary amines.2"1 0 The methods of Eqs. 4.20 and 4.21 have some merits over the conventional methods, for variously substituted (3-nitro-aldehydes acetals or nitroenamines are readily prepared by these methods. 

The conversion of primary or secondary nitro compounds into aldehydes or ketones is normally accomplished by use of the Nef reaction, which is one of the most important transformations of nitro compounds. Various methods have been introduced forthis transformation (1) treatment of nitronates with acid, (2) oxidation of nitronates, and (3) reduction of nitroalkenes. Although a comprehensive review is available,3 important procedures and improved methods published after this review are presented in this chapter. The Nef reaction after the nitro-aldol (Henry reaction), Michael addition, or Diels-Alder reaction using nitroalkanes or nitroalkenes has been used extensively in organic synthesis of various substrates, including complicated natural products. Some of them are presented in this chapter other examples are presented in the chapters discussing the Henry reaction (Chapter 3), Michael addition (Chapter 4), and Diels-Alder reaction (Chapter 8). 

The base-catalyzed reaction of nitroalkanes and sugar-based aldehydes (the Henry reaction) is one of the most common procedures for the lengthening of the carbon skeleton of a carbohydrate.16 The mild reaction conditions required for the formation of C C bonds by this method are usually compatible with most of the protective groups and masked functionalities involved in multistep synthesis from sugars.17... 

Nitroaldol (Henry) reactions of nitroalkanes and a carbonyl were investigated by Hiemstra [76], Based on their earlier studies with Cinchona alkaloid derived catalysts, they were able to achieve moderate enantioselectivities between aromatic aldehydes and nitromethane. Until then, organocatalyzed nitroaldol reactions displayed poor selectivities. Based on prior reports by Sods [77], an activated thionrea tethered to a Cinchona alkaloid at the quinoline position seemed like a good catalyst candidate. Hiemstra incorporated that same moiety to their catalyst. Snbsequently, catalyst 121 was used in the nitroaldol reaction of aromatic aldehydes to generate P-amino alcohols in high yield and high enantioselectivities (Scheme 27). 

Ooi has recently reported application of chiral P-spiro tetraaminophosphonium salt 37 as a catalyst for the highly enantio- and diasterioselective direct Henry reaction of a variety of aliphatic and aromatic aldehydes with nitroalkanes (Scheme 5.51) [92]. Addihon of the strong base KO Bu generates in situ the corresponding catalyhcally active triaminoiminophosphorane base A. Ensuing formation of a doubly hydrogen-bonded ion pair B positions the nitronate for stereoselective addition to the aldehyde. This catalyst system bears many similarities to guanidine base catalysis. 

The compound 3 can be easily prepared, in one pot, through a solvent-free procedure by nitroaldol reaction of nitroalkane 1 (2.2 mmol) and aldehyde 2 (2.2 mmol, freshly distilled), on activated neutral alumina (0.6 g, the alumina was added to a mechanically stirred solution of 1 and 2, at 0°C, then at room temperature for 20 h). Then, in situ addition (0°C) of wet-alumina supported chro-mium(VI) oxide (0.88 g (8.8 mmol) of C1O3 and 2.64 g of wet alumina). After standing for additional 20 h, the product was extracted with diethyl ether and passed through a bed of alumina. Evaporation of the organic solvent and flash chromatographic purification afforded the pure a-nitro ketone 3 in good yields (68-86%). 

Nitroalkanes are the key starting precursors for the formation of C-C bond by reactions with aldehydes (nitroaldol-Henry reaction) and electron-poor alkenes (Michael... 

Caldarelli et al. (240) have recently reported a five-step synthesis of substituted p)Trole libraries L22 and L23 using solid-supported reagents and scavengers. The synthesis involved oxidation of benzyl alcohols Mi to aldehydes (step a, Fig. 8.46), Henry reaction of aldehydes 8.91 with nitroalkanes M2 (step b), and acylation and elimination of nitroalcohols 8.93 (steps c and d) to give the nitrostyrenes 8.94, which were subjected to 1,3-dipolar cycloaddition with an isocyanoacetate (step e) to give the pyrroles 8.95. N-alkylation of these pyrroles with alkyl halides (step f) and final library-from-a-library hydrolysis/decarboxylation of L22 gave a library of trisub-stituted pyrroles L23 (step g. Fig. 8.46). 

When aromatic aldehydes are condensed with nitroalkanes in the presence of a base, a, p-unsaturated nitro compounds are produced directly. For example, benzaldehyde and nitromethane in the presence of a base give a,p-unsaturated compound nitrostyrene (3.25). Similarly, the reaction of nitrobutane with furfural in the presence of a base followed by hydrolysis gives 82% yield of 2-substituted furan derivative 3.26. 

Schemes 51-54) - (xiii) a-metallovinyl selenoxides (Scheme 179) (xiv) a-metalloalkyl selenones (Schemes 55 and 56) i29,i30,i38,206 gjjjj v) a-selenometalloenolates derived from esters (Scheme 10), lactones (Scheme 38), lactams - including B-lactams (Scheme 42, a Scheme 99), and nitroalkanes (Scheme 41). Most of the organometallics listed produce the corresponding alcohols by reaction with aldehydes and ketones and further hydrolysis of the resulting alcoholates. 

The a-hydrogens of nitroalkanes are appreciably acidic due to resonance stabilization of the anion [CH3NO2, 10.2 CH3CH2NO2, 8.5]. The anions derived from nitroalkanes give typical nucleophilic addition reactions with aldehydes (the Henry-Nef tandem reaction). Note that the nitro group can be changed directly to a carbonyl group via the Nef reaction (acidic conditions). Under basic conditions, salts of secondary nitro compounds are converted into ketones by the pyridine-HMPA complex of molybdenum (VI) peroxide. Nitronates from primary nitro compounds yield carboxylic acids since the initially formed aldehyde is rapidly oxidized under the reaction conditions. 

Condensations. Alumina promotes the formation of a-hydroxyphosphonate esters from aromatic aldehydes and dialkyl phosphonates, and the adducts are converted to a-aminophosphonate esters on reaction with ammonia. A solvent-free synthesis of a-nitro ketones comprises mixing nitroalkanes, aldehydes, and neutral alumina and oxidizing the adducts with wet, alumina-supported CrOj (15 examples, 68-86%). The Knoevenagel reaction, the Michael addition of nitromethane to gcm-diactivated alkenes, and the formation of iminothiazolines from thioureas and a-halo ketones are readily effected with alumina under microwave irradiation. 

Alkylation solves the awkward problem of how to make aryl ketones of the pattern 151, awkward because the Friedel-Crafts reaction doesn t work with this substitution pattern. Alkylation of a nitroalkane with the benzylic halide 149 does work well and the product 150 can be oxidised to the ketone32151. Reactions with aldehydes work even with masked aldehydes33 like dihydropyran to give 154 and hence the ketone 155 with a 1,2-substitution pattern after hydrolysis.34 More vigorous conditions give nitroalkenes 145 from aldehydes and these will be very useful later as a2 reagents. 

---